Synthesis of bisindolylmaleimides

ABSTRACT

The present invention provides a novel synthesis of the compounds of Formula (I): ##STR1## The compounds are produced in high yield and without utilizing expensive chromatographic separations. The synthesis is particularly advantageous because it is stereoselective.

This application is a division of application Ser. No. 08/452,613 filedMay 25, 1995, now U.S. Pat. No. 5,614,647 which is a division ofapplication Ser. No. 08/317,140, now U.S. Pat. No. 5,541,347, filed Oct.3, 1994 which is a continuation-in-part of Heath, et al., U.S. Ser. No.08/163,060, filed Dec. 7, 1993, now abandoned.

BACKGROUND OF THE INVENTION

Therapeutically, an antagonist which possesses both kinase selectivityfor protein kinase C (PKC) and PKC isozyme Selectivity is a potentiallyuseful pharmacological agent. Hartenstein, J. H., et al., in"perspectives in Medicinal Chemistry," 99-118 (1993), VCH Publishers,New York. Such an antagonist of protein kinase C would be useful intreating disease states in which PKC has been implicated. Lester, D. S.,et al., "Protein Kinase C: Current concepts and Future Perspectives",Ellis Horwood New York (1992). Specific isozymes of protein kinase Chave been implicated in cancer (Ahmed, et al., Mol, Pharma., 43, 858-86(1993), CNS diseases such as Alzheimer's; Demaerschalck, et al.,Biochem. Biophys. Acta. 1181, 214-218 (1993), cardiovascular disease;(Natarajan et al. Mol. Cell. Endo., 101, 59-66 (1994)) and diabeticcomplications; King, et al., Proc. Nat. Acad. Sciences (USA), 88:22,11059-63 (1992).

Recently, bisindolylmalimides of the formula: ##STR2## have beenrecognized as PKC selective agents and have shown promise as therapeuticagents for treating diseases implicated by PKC. Bit, et al., J. Med.Chem, 56:21 (1993). Wikinson S. E., et al., Biochem J., 299, 335 (1993).Toullec, D., et al., J. Biol. Chem., 266, 15771 (1991); Davis, P. D., etal., J. Med. Chem., 35, 177 (1992).

U.S. patent application Ser. No. 08/163,060 discloses a novel class ofcompounds that are potent and effective inhibitors of PKC. Thesecompounds are of the Formula (I): ##STR3## and are prepared by couplinga bisindolylmaleimide with a linker of the Formula (II): ##STR4## toform the N to N linked bisindolylmaleimide.

The present invention provides novel compounds of the Formula (II) andthe stereoselective synthesis of these compounds. Under the preferredconditions, the compounds are produced in high yield and withoututilizing expensive chromatographic separations. The synthesis isparticularly advantageous because it further provides a stereoselectiveroute of preparing the compounds of the Formula (I).

SUMMARY OF THE INVENTION

The invention provides Compounds of the Formula: ##STR5## wherein: R² isN₃, NH-protecting group, amine protecting group, or hydroxy protectinggroup;

L¹ is independently a leaving group;

Z is --(CH₂)_(n) --; and

n is independently 1, 2, or 3.

The invention further provides a stereoselective process of preparingthese compounds, which comprises:

(a) Alkylating a compound of Formula (III): ##STR6## with a lithiumacetylide, a cerium acetylide, or a vinyl organometalic reagent selectedfrom vinyl cuprate, vinyl aluminum, vinyl tin, vinyl lithium, or vinylGrignard;

to produce a compound of the Formula (IV): ##STR7## (b) reacting acompound of the Formula (IV) with a compound of the Formula: ##STR8##wherein R³ is halo, a protected hydroxy, or combines with the adjacentcarbon to form an olefin; R⁴ is chloro, bromo, or iodo;

to form a compound of the Formula (V) ##STR9## (c) converting thecompound of the Formula (V) to a compound of the Formula (II).

Compound (II) is useful in the preparation of the compounds of theFormula (I), which are potent PKC inhibitors.

DETAILED DESCRIPTION AND PREFERRED EMBODIMENTS

As noted above, the invention provides a novel synthesis for thepreparation of a compound of the Formula (II): ##STR10## Particularlypreferred compounds of the Formula II are when L¹ and L¹ are the sameand are mesyl or iodo; n is 1; and R² is --O-trityl or --O-mono- ordi-methoxytrityl.

Compound II is useful for the preparation of compounds of Formula I:##STR11## wherein: Z is --(CH₂)_(n) --;

R is independently hydrogen, halo, C₁ -C₄ alkyl, hydroxy, C₁ -C₄ alkoxy,haloalkyl, nitro, NR⁵ R⁶, or --NHCO(C₁ -C₄ alkyl );

R¹ is C₁ -C₄ alkyl, C₁ -C₄ alkoxy, (CH₂)_(m) aryl, (CH₂)_(m) aryloxy,hydroxy, carboxy, --COO(C₁ -C₄ alkyl) ), --COO((CH₂)_(m) aryl), --CO(C₁-C₄ alkyl ), --NR⁵ R⁶, --(NR⁵ R⁶ ) (OR⁵), --NH(CH₂)_(m) aryl,--NH(CH₂)_(m) pyridyl, --CONH((CH₂)_(m) aryl ), --CONH(C₁ -C₄ alkyl),--NHCO(C₁ -C₄ alkyl), --NHCO(CH₂)_(m) aryl, --OCONH(C₁ -C₄ alkyl),--OCONH(CH₂)_(m) aryl, --NHCOO(alkyl), --NHCOO(benzyl), --NHSO₂ (C₁ -C₄alkyl), --NHSO₂ (CH₂)_(m) aryl, --CN, --SH, --S(C₁ -C₄ alkyl),--S(aryl), --SO₂ (NR⁵ R⁶), --SO₂ (C₁ -C₄ alkyl), or --SO(C₁ -C₄ alkyl);

R⁵ and R⁶ are independently hydrogen, methyl, phenyl, benzyl, or combineto the nitrogen to which they are bonded to form a saturated orunsaturated 5 or 6 membered ring; and

m is independently 0, 1, 2 or 3.

The most preferred compounds of the Formula I are those wherein R ishydrogen; R¹ is NR⁵ R⁶ ; n is 1; m is 1; and R⁵ and R⁶ are methyl.

Compounds of the Formula I are disclosed in U.S. patent application Ser.No. 08/163,060. As PKC inhibitors, the compounds are useful for treatingconditions that protein kinase C has demonstrated a role in thepathology, such as ischemia, inflammation, central nervous systemdisorders, cardiovascular disease, dermatological disease, cancer and,in particular, diabetes mellitus.

The term "halo", as used herein, represents fluorine, chlorine, bromine,or iodine.

The term "C₁ -C₄ alkyl" represents a cyclo, straight or branched chainalkyl group having from one to four carbon atoms such as methyl, ethyl,n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, t-butyland the like. A haloalkyl is one such alkyl substituted with one or morehalo atoms, preferably one to three halo atoms. An example of ahaloalkyl is trifluoromethyl. A C₁ -C₄ alkoxy is a C₁ -C₄ alkyl groupcovalently bonded by an --O-- linkage.

The term "aryl" represents a substituted or unsubstituted phenyl ornaphthyl. Aryl may be optionally substituted with one or two groupsindependently selected from hydroxy, carboxy, C₁ -C₄ alkoxy, C₁ -C₄alkyl, haloalkyl, nitro, --NR⁵ R⁶, --NHCO(C₁ -C₄ alkyl), --NHCO(benzyl),--NHCO(phenyl), SH, S(C₁ -C₄ alkyl), --OCO(C₁ -C₄ alkyl), --SO₂ (NR⁵R⁶), --SO₂ (C₁ -C₄ alkyl), --SO₂ (phenyl), or halo. The term aryloxy isone such aryl covalently bonded by an --O-- linkage. The term (CH₂)_(m)aryl is preferably benzyl or phenyl.

The term "leaving group" as used in the specification is understood bythose skilled in the art. Generally, a leaving group is any group oratom that enhances the electrophilicity of the atom to which it isattached for displacement. Preferred leaving groups are trillate,mesylate, tosylate, imidate, chloride, bromide, and iodide.

The term "hydroxy protecting group" as used in the specification refersto one of the ether or ester derivatives of the hydroxy group commonlyemployed to block or protect the hydroxy group while reactions arecarried out on other functional groups on the compound. The species ofhydroxy protecting group employed is not critical so long as thederivatized hydroxy group is stable to the condition of subsequentreaction(s) and can be removed at the appropriate point withoutdisrupting the remainder of the molecule. T. W. Greene and P. Wuts,Protective Groups in Organic Synthesis, John Wiley and Sons, New York,N.Y., 1991, provide a list of commonly employed protecting groups.Preferred hydroxy protecting groups are tert-butyldiphenylsilyloxy(TBDPS), tert-butyldimethylsilyloxy (TBDMS), triphenylmethyl (trityl,mono- or di-methoxytrityl, or an alkyl or aryl ester. A related term is"protect hydroxy," which refers to a hydroxy group substituted with ahydroxy projecting group.

The term "amino protecting group" as used in the specification refers tosubstituents of the amino group commonly employed to block or protectthe amino functionality while reacting other functional groups on thecompound. The species of amino-protecting group employed is not criticalso long as the derivatized amino group is stable to the condition ofsubsequent reaction(s) and can be removed at the appropriate pointwithout disrupting the remainder of the molecule. T. W. Greene and P.Wuts, Protective Groups in Organic Synthesis, Chapter 7, provide a listof commonly employed protecting groups. See also J. W. Barton,Protective Groups in Organic Chemistry, Chapter 2. Preferredamino-protecting groups are t-butoxycarbonyl, phthalimide, an --NHcyclic alkyl, and benzyloxycarbonyl. The related term "protected amino"defines an amino group substituted with an amino protecting group aspreviously defined.

The term "--NH protecting groups" as used in the specification refers tosub-class of amino protecting groups that are commonly employed to blockor protect the --NH functionality while reacting other functional groupson the compound. The species of protecting group employed is notcritical so long as the derivatized amino group is stable to thecondition of subsequent reaction(s) and can be removed at theappropriate point without disrupting the remainder of the molecule. T.W. Greene and P. Wuts, Protective Groups in Organic Synthesis, Chapter7, page 362-385, provide a list of commonly employed protecting groups.Preferred --NH protecting groups are carbamate, amide, alkyl or arylsulfonamide. The related term "protected --NH" defines an --NH groupsubstituted with an --NH protecting group as defined.

The synthesis of the macrocycles of Formula I is carried out as follows:##STR12##

In the above scheme, R⁷ is methyl or hydrogen. R and m are the same aspreviously defined. The reaction illustrated in Scheme 1 is oftenreferred to as a Grignard reaction. The reaction is generally describedby Brenner, et al., Tetrahedron, 44, 2887-2892 (1988). Generally, thereaction of Scheme 1 is carried out in an inert solvent such as benzene,toluene, tetrahydrofuran or ether at a temperature between roomtemperature and reflux temperature of the reaction mixture. Compound(VII) is preferably prepared in situ from the indole and an alkylmagnesium halide such as ethyl magnesium bromide or ethyl magnesiumiodide in a manner known in the art.

Most significantly, the reaction depicted in Scheme 1 is dependent onsolvent conditions. When carried out in a Toluene:THF:ether solventsystem the reaction of Scheme 1 provides Compound VIII in greater than80 percent yield and greater than 95 percent purity. The product isprecipitated from the reaction mixture with ammonium chloride, NH₄ Cl.

The linker portion of the macrocycles of Formula (I) is prepared inaccordance with Scheme 2. ##STR13##

Z, R², R³, R⁴, and n are the same as previously defined. Scheme 2presents a stereoselective synthesis of the linker portion of themacrocycle. The S-enantiomer is illustrated above; however, one skilledin the art would recognize that the complimentary enantiomer, or amixture of enantiomers could be prepared in an analogous manner.

The regioselective opening of epoxide, Compound (III), is carried out byalkylating a compound of Formula (III): ##STR14## with a lithiumacetylide, a cerium acetylide, or organometalic reagent selected fromvinyl cuprate, vinyl aluminum, vinyl tin, vinyl lithium, or vinylGrignard. Preferably, a vinyl organometalic reagent is a compound of theformula: vinyl MgBr, vinyl MgCl, vinyl Li, vinyl(thienyl)Cu(CN)Li₂,Vinyl(thienyl)Cu(CN)LiMgBr, or a lithium acetlyene:EDTA complex.

The reaction between the epoxide (III) and the organometalic occursunder conditions appreciated in the art. The reaction between a vinylGrignard and an epoxide in the presence of a catalytic cuprate isdescribed in Tius M. A., et al., J. Am. Chem. Soc. 108(5): 1035-1039(1986) and DeCampshuda A. et al. Synthesis-Stuttgart (4), 309-312(1986). Likewise, Gillet J. P. et al., Synthesis-Stuttgart (5), 355-360(1986) describe the use of a vinyl lithium reagent in the presence of alewis acid to open the epoxide; Lipshutz B. H., et al., TetrahedronLett. 29(8): 893-896 (1988) disclose higher order cuprates to open vinylepoxides; Behling J. R., Tetrahedron Lett. 30(1): 27-30 (1989) disclosestannyl or vinyl tin reagents useful to open the epoxide; Alexakis A.,et al., Tetrahedron 45(19): 6197-6202 (1989) disclose the use of a vinylaluminate to open the epoxide; and the lithium acetylide reduction ofthe epoxide is disclosed in Synthesis, 139-141 (1987). When carried outwith lithium acetylide or a cerium acetylide, an additional reductionwith H₂ /Lindlar's catalyst is necessary to produce the allyl, CompoundIV.

Preferably, the reaction is carried out with vinyl MgBr or MgCl in thepresence of a catalytic cuprate such as CuI or CuBr. The reaction iscarried out in an inert solvent at a temperature between about -80° C.to the reflux temperature of the reaction mixture; preferably thetemperature is -20° C. to 30° C. The reaction produces Compound (IV)which may be further reacted without purification.

Compound IV is alkylated or allylated under conditions appreciated inthe art for coupling an alcohol to a alkyl or allyl halide to form theether, Compound (V): ##STR15## The reaction is commonly known as theWilliamson Synthesis. The reaction involves a nucleophilic substitutionof an alkoxide ion with the halide ion (R⁴). The alkoxide ion ispreferably generated in the presence of a base such as NaOH, KOH, or NaHin an aprotic solvent such as DMSO, THF, DMF, ether, or toluene.

Compound (V) is converted to Compound (II) by techniques appreciated inthe art. For example, when R³ is an olefin such as ═CR⁸ R⁹ wherein R⁸and R⁹ are independently hydrogen, aryl, or C₁ -C₄ alkyl, Compound (V)is converted to an ozonide by treating with ozone at low temperatures.The ozonide is then reduced with NaBH₄, LiAlH₄, BH₃ or catalytichydrogenation with excess H₂ to produce a hydroxy moiety. The hydroxymay be readily converted to leaving group L¹. For example, the mesylleaving group is prepared by reacting the hydroxy with methanesulfonylchloride in triethylamine. Alternatively, the free hydroxy is convertedto a iodide or bromide leaving group using, for example, CBr₄ intriphenylphosphine.

One skilled in the art would recognize that the reaction of Scheme 2 isparticularly advantageous when R³ is ═CH₂. Both double bonds may beconverted to the ozonide and reduced simultaneously to produce a diol,which is readily converted to Compound (II) wherein both L¹ moleties arethe same leaving group.

The preparation of Compound (II) in a manner described is anadvantageous means of preparing Compound (II) in high yield. The processis efficient and suitable for large scale. The synthesis is particularlyadvantageous when R² is a protected hydroxy, specifically O-trityl. WhenR² is O-trityl, Compound II may crystallized from the reaction mixturethus avoiding expensive chromatographic steps. When R² is TBDPS or otherprotecting group, crystallization and purification are more difficultand expensive. The ability to produce a crystalline compound in highyield and purity without expensive chromatographic steps is clearlyadvantageous over other means of synthesizing Compound (II).

Compound (II) is coupled to Compound (VIII) as described in Scheme 3.##STR16##

The reaction represented by Scheme 3 is accomplished by any of the knownmethods of preparing N-substituted indoles. This reaction usuallyinvolves approximately equimolar amounts of the two reagents, althoughother ratios, especially those wherein the alkylating reagent is inexcess, are operative. The reaction is best carried out in a polaraprotic solvent employing an alkali metal salt or other such alkylationconditions as are appreciated in the art. When the leaving group isbromo or chloro, a catalytic amount of iodide salt, such as potassiumiodide may be added to speed the reaction. Reaction conditions includethe following: Potassium hexethyldisilazide in dimethylformamide ortetrahydrofuran, sodium hydride in dimethylformamide.

Preferably, the reaction is carried out under slow reverse addition withcesium carbonate in either acetonitrile, dimethylformide (DMF), ortetrahyofuran (THF). Slow reverse addition involves containing a mixtureof Compound (VIII) and alkylating agent (II) with the base at a ratefrom about 0.1 mL/hour to about 2.0 ml/hour. The concentration of eachreagent in the mixture is about 1.5 molar to about 0.001 molar. The slowaddition results in a concentration of reagents in the reaction vesselof about 0.01 μmolar to 1.5 molar. One skilled in the art wouldrecognize that at a higher rate of addition a lower concentration ofreagents could be used in the reaction. Likewise, at a slower rate ofaddition, a higher concentration of reagents could be used in thereaction. Preferably, the compound is added at about 0.14 mL/hour withthe compound and the alkylating agent at 0.37 molar. It is preferredthat the Cs₂ CO₃ be added in excess--most preferably a 4:1 ratio Cs₂ CO₃to alkylating agent. Preferred polar aprotic solvents are acetonitrile,dimethylformamide (DMF), acetone, dimethylsulfoxide (DMSO), dioxane,diethylene glycol methyl ether (diglyme), tetrahydrofuran (THF), orother polar aprotic solvents in which the reagents are soluble. Thereaction is carried out at temperatures ranging from about 0° C. toreflux.

One skilled in the art would recognize that the ratio of the mixture ofthe compound and alkylating agent is not critical. However, it ispreferred that the reagents are mixed in a ratio of 0.5 to 3 equivalentsof each other. Most preferably, the reagents are mixed 1:1. Theconcentration of compound in the dissolving solvent is from saturationto about 0.01M.

Compound (XIII) is converted to the compound of the Formula I throughthe corresponding anhydride by an alkaline hydrolysis known in the art.Alkaline hydrolysis involves reacting the Compound (XIII) with a base,such as sodium hydroxide or potassium hydroxide, in C₁ -C₄ alcohol(preferably ethanol), DMSO/water, dioxane/water, or acetonitrile/waterat a temperature ranging from about 25° C. to preferably about reflux.The concentration of the reactants is not critical.

The anhydride is converted to the maleimide of Formula I by ammonolysis.Ammonolysis involves reacting the anhydride with an excess ofhexamethyldisilazane or an ammonium salt (ammonium acetate, bromide, orchloride) and C₁ -C₄ alcohol (preferably methanol) in an polar aproticsolvent such as DMF at room temperature. Preferably, thehexamethyldisilazane or an ammonium salt is reacted at a ratio greaterthan about 5:1 equivalents of anhydride.

The conversion of R² to the desired R¹ moiety is carried out bytechniques known in the art for deprotecting an amine or hydroxy. Forexample, when R² is --O-trityl, the compound is de-tritylated with HClgas in methylene chloride. The resulting hydroxy or amine may then beconverted to the various substitutions of R¹ under standard conditions.For example, when R² is hydroxy, R² is converted to the mesylate withMS₂ O and pyridine in THF and subsequently converted to thedimethylamine or other amine substitution.

As previously stated, the present process is useful in preparingcompounds of the Formula I. The compounds of the Formula I are PKCinhibitors and useful in treating diseases implicated by PKC. Thecompounds of Formula I inhibit PKC with an IC₅₀ of below 100 μm. Inaddition, the compounds selectively inhibit the beta-1 and beta-2 PKCisozymes and have an IC₅₀ value with respect to these isozymes of below10 μm. The amount of compound administered is an amount that is capableof inhibiting PKC activity in mammals. The particular dose of thecompound administered according to this invention will, of course, bedetermined by the particular circumstances surrounding the case,including the compound administered, the route of administration, theparticular condition being treated, and similar considerations. Thecompounds of Formula I can be administered by a variety of routesincluding the oral, rectal, transdermal, subcutaneous, topical,intravenous, intramuscular or intranasal routes. For all indications, atypical daily dose will contain from about 0.01 mg/kg to about 20 mg/kgof the active compound of this invention. Preferred daily doses will beabout 0.05 to about 10 mg/kg, ideally about 0.1 to about 5 mg/kg.However, for topical administration a typical dosage is about 1 to about500 μg compound per cm² of an affected tissue. Preferably, the appliedamount of compound will range from about 30 to about 300 μg/cm², morepreferably, from about 50 to about 200 μg/cm², and, most preferably,from about 60 to about 100 μg/cm².

The following examples and preparations are provided merely to furtherillustrate the invention. The scope of the invention is not construed asmerely consisting of the following examples. In the following examplesand preparations, melting point, nuclear magnetic resonance spectra,mass spectra, high pressure liquid chromatography over silica gel,N,N-dimethylformamide, palladium on charcoal, tetrahydrofuran, and ethylacetate are abbreviated M.Pt., NMR, MS, HPLC, DMF, Pd/C, THF, and EtOAcrespectively. The terms "NMR" and "MS" indicate that the spectrum wasconsistent with the desired structure.

PREPARATION 1 Dichloro-N-methylmaleimide

A 3 L-three-necked flask fitted with a magnetic stir bar, digitalthermocouple/thermometer, nitrogen purge and solid addition funnel wascharged with 450 g (269.5 mol) of dichloromaleic anhydride, 191 g (282.8mol) of methylamine hydrochloride and 1.6 L of acetic acid. The reactionmixture was then cooled to 10° C., and 160 g NaOMe added from the solidaddition funnel over 1 hour while keeping the temperature between10°-12° C. The reaction was allowed to stir at room temperature for 42hours (24 hours is sufficient) then heated to 100° C. for 3 hours. HPLCanalysis at this time indicated that all the starting material haddisappeared. The reaction was cooled to room temperature and 2 L waterwas added. The mixture was then cooled to 3°-10° C. for 1 hour andfiltered at 4° C. The solids were then rinsed with 2 L of cold deionizedwater. The pale yellow solid dried in an air oven overnight to afford360 g (75%) yield of the titled compound 316726.

PREPARATION 2 (S)-Trityl Glycidol

Trityl chloride (2866 g, 10.3 mole) was dissolved in 7 L of CH₂ Cl₂under N₂. Triethylamine (1189 g, 1638 mL, 11.8 mole) was added, and then(R)-(-)-glycidol 329791(795.0 g, 10.6 mole) was added using 1 L of CH₂Cl₂ as a rinse. The reaction solution was heated to a gentle reflux (42°C.) for 3-4 hours. The reaction was cooled to room temperature and then3 L of brine was added. The organic layer was dried (600 g Na₂ SO₄) andevaporated in vacuo to give the titled compound as an oil that wasrecrystallized from ethanol to give 2354 g (70%) of the titled compoundas a solid.

PREPARATION 3 2,3-Bis-(1H-indol-3-yl)-N-methylmaleimide

Indole (157.4 g, 1.343 mol, 2.2 eq.), toluene (2.28 L), and THF (412 mL)were charged to a 12 L reaction flask equipped with mechanical stirrer,thermocouple/Hastelloy probe, temperature controller, heating mantle,condenser, 500 mL addition funnel, and nitrogen inlet. The colorlesssolution was stirred briefly at ambient temperature under nitrogen.

3.0M EtMgBr solution in Et₂ O (452 mL, 1.36 mol, 2.2 eq.) was charged tothe addition funnel and added dropwise over 30 minutes to the indolesolution, during which time an exotherm to 53° C. was observed. The palegreen solution was heated to 60° C. and held there for 1 hour.

A solution of dichloro-N-methylmaleimide (110.0 g, 0.611 mol, 1.0 eq.)in toluene (578) mL was prepared and added streamwise to the reactionmixture over 5-10 minutes, during which time an exotherm to 67° C. and adark heterogeneous mixture resulted. The mixture was heated to a gentlereflux (88° C.) and held there overnight until completed by HPLC.

The reaction mixture was cooled to 20°-30° C. Saturated ammoniumchloride solution (1.76 L) was added, dropwise initially, until theexotherm to 35°-40° C. subsided, at which point the dark heterogeneousmixture converted to a red slurry. The slurry was stirred at 25°-30° C.for 2-4 hours. The product was isolated by filtration, rinsed with waterand toluene, then dried in a vacuum oven at 50° C. 168 grams (80%) ofproduct was obtained.

PREPARATION 41-(tert-butyldimethylsilyloxy)-4-(tert-butyldiphenylsilyloxy)-butan-2-ol

To an anhydrous CH₂ Cl₂ (110 mL) solution of 3-buten-1-ol (15 g, 0.21mol) was added imidazole (28.6 g, 0.42 mol, 2 eq), followed bytert-butyldimethylsilyl chloride (32 g, 0.22 mol). After 90 minutes, thereaction was complete as indicated by TLC (10% EtOAc/hexane). The CH₂Cl₂ solution was transferred to a separatory funnel, diluted with CH₂Cl₂ (110 mL), washed with water (200 mL), and brine (200 mL). Theorganic layer was collected, dried over MgSO₄, and filtered. The solventwas removed to yield an oil (1-(O-TBDMS)-3-butene) which was taken on tothe next reaction. MS

The above oil was dissolved in a mixture of acetone (400 mL) and water(50 mL). N-Methylmorpholine-N-oxide (85.2 g, 0.63 mol, 3 eq) was thenadded. The resulting slurry was cooled to 0° C., and after 10 minutes acatalytic amount of OsO₄ (0.3 g) was added. The resulting slurry wasallowed to stir overnight, gradually warming to room temperature. TLC(25% EtOAc/hexane) indicated the reaction was complete. The reactionmixture was quenched with sodium bisulfite, diluted with ether (1 L),washed with water (400 mL), and brine (400 mL). The organic layer wascollected. The aqueous layer extracted with ether (2×500 mL). Thecombined organic layers were dried, filtered, and concentrated to yield4-(O-TBDMS)-1,2-butanediol as an oil, which was taken on to the nextreaction.

The above oil was dissolved in anhydrous CH₂ Cl₂ (250 mL). Imidazole (30g, 0.44 mol, 2.5 eq) was added to the solution as a solid with stirring.The resulting solution was cooled to 0° C. After cooling 15 minutes, aCH₂ Cl₂ (50 mL) solution of tert-butyldiphenylsilyl chloride (50 g, 0.18mol, 1 eq) was added dropwise over 45 minutes. After the addition wascomplete, stirring was continued at 0° C. for 2.5 hours. The solutionwas transferred to a separatory funnel, diluted with CH₂ Cl₂ (250 mL),washed with water, brine, dried over MgSO₄, and filtered. The solventremoved under reduced pressure to give the crude product as an oil. Thecrude product was purified by eluting (10% EtOAc/hexane) it through ashort column of silica gel. The eluting solvent was removed in vacuo toleave a viscous oil of the titled intermediate. (78.1 g, 93 % overallyield). MS ##STR17##

EXAMPLE 1 (326755)(S)-13-[(dimethylamino)methyl]-10,11,14,15-tetrahydro-4,9:16-21-dimetheno-1H,13H-dibenzo[E,K]pyrrolo[3,4-H][1,4,13]oxadiazacyclohexadecine-1,3(2H)-dione

2,3-Bis-(1H-indol-3-yl)-N-methylmaleimide (114.7 g, 0.336 mole) and(S)-3-[2-[(methylsulfonyl)oxy]ethoxy]-4-(triphenylmethoxy)-1-butanolmethane sulfonate (220.0 g, 0.401 mole, 1.2 eq.) were dissolved in 4.3 Lof DMF. This solution of reagents was then added slowly over 70 hours(at approximately 1 mL/min) to a 50° C. slurry of cesium carbonate(437.8 g, 1.34 mole, 4.0 eq.) in 7 L of DMF. After 70-72 hours thereaction was cooled and filtered, and the DMF was removed in vacuo togive a residue that was dissolved in 4.6 L of CH₂ Cl₂. The organic layerwas extracted with 1.15 L of aqueous 1N HCl and then with 4.6 L ofbrine. The combined aqueous layers were back-extracted with 1.1 L of CH₂Cl₂. The combined organic layer was dried (Na₂ SO₄) and filtered. Mostof the solvent was removed in vacuo, and the resultant solution wasfiltered through 2 Kg of silica gel using 4-5 gallons of additional CH₂Cl₂ to remove baseline material. The solvent was removed in vacuo andthe resultant purple colored solid triturated in 7 volumes ofacetonitrile (based on weight of crude(S)-10,11,14,15-tetrahydro-2-methyl-13-[(triphenylmethoxy)methyl]-4,9:16,21-dimetheno-1H,13H-dibenzo[E,K]pyrrolo[3,4-H][1,4,13]oxadiazacyclohexadecine-1,3(2H)-dioneto give 150.2 g (57%) of(S)-10,11,14,15-tetrahydro-2-methyl-13-[(triphenylmethoxy)methyl]-4,9:16,21-dimetheno-1H,13H-dibenzo[E,K]pyrrolo[3,4-H][1,4,131]oxadiazacyclohexadecine-1,3(2H)-dioneafter drying (89% pure by HPLC vs. standard).

(S)-10,11,14,15-tetrahydro-2-methyl-13-[(triphenylmethoxy)methyl]-4,9:16,21-dimetheno-1H,13H-dibenzo[E,K]pyrrolo[3,4-H][1,4,13]oxadiazacyclohexadecine-1,3(2H)-dione(32.7 g, 46.9 mmol) was suspended in 1.6 L of ethanol and 1.6 L ofaqueous 10N KOH. The resultant mixture was heated to a gentle reflux(78° C.) for 19 hours. Most of the solids dissolved upon reachingreflux. The reaction solution was cooled to 10° to 15° C. and aqueous10N HCl (1.2 L) was slowly added at <15° C. to adjust the acidity topH=1. A red slurry developed upon acidification. The reaction mixturewas diluted with 500 mL of CH₂ Cl₂ and was stirred for 20 minutes andfiltered to remove most of the salts. The salts were washed withadditional CH₂ Cl₂ (1.5 L), and the filtrate was extracted twice with 1L of water. The combined aqueous layers were back-extracted with 1 L ofCH₂ Cl₂, and the organic layer was dried (MgSO₄). The solvent wasremoved in vacuo to give 36.0 g (>100%)(S)-10,11,14,15-tetrahydro-13-[(triphenylmethoxy)methyl]-4,9:16,21-dimetheno-13H-dibenzo[E,K]furo[3,4-H][1,4,13]oxadiazacyclohexadecine-1,3-dioneas a purple solid (80% pure by HPLC area).

(S)-10,11,14,15-tetrahydro-13-[(triphenylmethoxy)methyl]-4,9:16,21-dimetheno-13H-dibenzo[E,K]furo[3,4-H][1,4,13]oxadiazacyclohexadecine-1,3-dione(36.0 g, assume 46.9 mmol) was dissolved in 320 mL of dry DMF under N₂and was treated with a pre-mixed solution of1,1,1,3,3,3-hexamethyldisilazane (99 mL, 75.7 g, 0.469 mol, 10 eq.) andmethanol (9.5 mL, 7.51 g, 0.235 mol. 5 eq.). The resultant solution washeated at 45° C. for 7 hours. The reaction can be monitored by HPLC.Most of the DMF was removed in vacuo, and the resultant residue wasextracted into 200 mL of ethyl acetate and washed with 200 mL of waterand twice with 100 mL of an aqueous 5% LiCl solution. The aqueous layerswere back-extracted with 100 mL of ethyl acetate. The combined organiclayer was washed with 200 mL of a saturated aqueous solution of ammoniumchloride. The combined organic layer was dried (MgSO₄) and evaporated invacuo to give 35.9 g (>100%) of the crude(S)-10,11,14,15-tetrahydro-13-[(triphenylmethoxy)methyl]-4,9:16,21-dimetheno-1H;13H-dibenzo[E,K]pyrrolo[3,4-H][1,4,13]oxadiazacyclohexadecine-1,3(2H)-dione as a purple solid. The35.9 g of crude(S)-10,11,14,15-tetrahydro-13-[(triphenylmethoxy)methyl]-4,9:16,21-dimeth-eno-1H;13H-dibenzo[E,K]pyrrolo[3,4-H][1,4,13]oxadiazacyclohexadecine-1,3(2H)-dionewas dissolved in 350 mL of acetone, cesium fluoride (4.0 g, 26.3 mmol,0.5 eq.) was added, and the resultant mixture was stirred for 1.5 hoursto remove the N-silyl derivative of(S)-10,11,14,15-tetrahydro-13-[(triphenylmethoxy)methyl]-4,9:16,21-dimeth-eno-1H;13H-dibenzo[E,K]pyrrolo[3,4-H][1,4,13]oxadiazacyclohexadecine-1,3(2H)-dione.The reaction mixture was filtered, and the cesium salts were washed withacetone. The solvent was removed in vacuo. The resultant residue (941 g)was diluted with 300 mL of ethyl acetate and was extracted with 150 mLof water with 25 mL of brine to improve layer separation. The organiclayer was then washed with 150 mL more water and the combined organiclayer was washed with 100 mL of brine, dried (MgSO₄) and was the solventremoved in vacuo to give 34.2 g (>100%)(S)-10,11,14,15-tetrahydro-13-[(triphenylmethoxy)methyl]-4,9:16,21-dimeth-eno-1H;13H-dibenzo[E,K]pyrrolo[3,4-H][1,4,13]oxadiazacyclohexadecine-1,3(2H)-dioneas a purple solid (90% pure by HPLC area).

(S)-10,11,14,15-tetrahydro-13-[(triphenylmethoxy)methyl]-4,9:16,21-dimeth-eno-1H;13H-dibenzo[E,K]pyrrolo[3,4-H][1,4,13]oxadiazacyclohexadecine-1,3(2H)-dione(34.0, assume 46.8 mmol) was dissolved in 350 mL of CH₂ Cl₂ and wascooled to -25° C. under N₂. Anhydrous HCl gas was bubbled into thereaction solution for approximately 1-2 minutes at <0° C. The resultantslurry was allowed to warm to room temperature and stir for 1 hour. Thereaction can be monitored by HPLC. The slurry was filtered and thesolids were washed with 200 mL of CH₂ Cl₂. The solid was dried in avacuum oven at 50° C. to give 18.6 g (90%)(S)-10,11,14,15-tetrahydro-13-(hydroxymethyl)-4,9:16,21-dimetheno-1H,13H-dibenzo [E,K]pyrrolo [3,4-H][1,4,13 ]oxadiazacyclohexadecine-1,3(2H) -dione as a purple solid (93% pure by HPLC area).

A suspension of(S)-10,11,14,15-tetrahydro-13-(hydroxymethyl)-4,9:16,21-dimetheno-1H,13H-dibenzo[E,K]pyrrolo[3,4-H][1,4,13]oxadiazacyclohexadecine-1,3(2H)-dione(18.2 g, 41.2 mmol) in 900 mL of THF was treated with pyridine (9.78 g,10.0 mL, 0.124 mmol, 3 eq.) and methanesulfonic anhydride (14.3 g, 80.4mmol, 2 eq.) and was heated to reflux (67° C.) for 16 hours under N₂.This reaction can be monitored by HPLC. The reaction was then cooled anddiluted with 600 mL of ethyl acetate and extracted twice with 300 mL of1N HCl and once with 600 mL of water. The aqueoues layers wereback-extracted with 300 mL of ethyl acetate and the organic layer dried(MgSO₄). The solvent was removed in vacuo to give 19.0 of(S)-10,11,14,15-tetrahydro-13-[[methylsulfonyl)oxy]methyl]-4,9:16,21-dimetheno-1H,13H-dibenzo[[E,K]pyrrolo[3,4-H][1,4,13]oxadiazacyclohexadecine-1,3(2H)-dionethat was triturated in 190 mL of hot (40° C.) CH₂ Cl₂ and was filteredhot and washed with 100 mL of additional room temperature CH₂ Cl₂ togive 17.3 g (81%) of(S)-10,11,14,15-tetrahydro-13-[[methylsulfonyl)oxy]methyl]-4,9:16,21-dimetheno-1H,13H-dibenzo[[E,K]pyrrolo[3,4-H][1,4,13]oxadiazacyclohexadecine-1,3(2H)-dioneas a purple solid (96% pure by HPLC area).

(S)-10,11,14,15-tetrahydro-13-[[methylsulfonyl)oxy]methyl]-4,9:16,21-dimetheno-1H,13H-dibenzo[[E,K]pyrrolo[3,4-H][1,4,13]oxadiazacyclohexadecine-1,3(2H)-dione(9.50 g, 18.3 mmol) was dissolved in 475 mL of THF and 172 mL of a 40%aqueous solution of dimethylamine (0.173 mole, 75 eq.) was added, theresultant solution was heated at 65° C. in a sealed reactor (8-10 psi.)for 19 hours. The reaction was cooled and diluted with 900 mL of ethylacetate and the organic layer was extracted twice with 450 mL of waterand once with 200 mL of brine. The aqueous layers were back-extractedwith 250 mL of additional ethyl acetate and the organic layer was dried(MgSO₄), and the solvent was removed in vacuo to give 7.82 g of(S)-13-[dimethylamino)methyl]-10,11,14,15-tetrahydro-4,9:16,21-dimetheno-1H,13H-dibenzo[E,K]pyrrolo[3,4-H][1,4,13]oxadiazacyclohexadecine-1,3(2H)-dione (91%).

(S)-13-[dimethylamino)methyl]-10,11,14,15-tetrahydro-4,9:16,21-dimetheno-1H,13H-dibenzo[E,K]pyrrolo[3,4-H][1,4,13]oxadiazacyclohexadecine-1,3(2H)-dione(3.0 g, 6.40 mmol) was suspended in 60 mL of type 3A ethanol and wascooled to -10° C. under N₂. Anhydrous HCl gas was bubbled into thereaction for approximately one minute at <10° C. and the resultantslurry allowed to warm and stir at room temperature for 2 hours. Theslurry was filtered and the solid was washed with 30 mL of ethanol togive 3.04 g (94%) of(S)-13-[(dimethylamino)methyl]-10,11,14,15-tetrahydro-4,9:16-21-dimetheno-1H,13H-dibenzo[E,K]pyrrolo[3,4-H[]1,4,13]oxadiazacyclohexadecine-1,3(2H)-dione monohydrochloride afterdrying.

¹ H NMR: (d₆ -DMSO) δ2.1 (m, 1H); 2.35 (m, 1H); 2.68 (s, 6H); 3.2 (m,1H,); 3.33 (m, 1H); 3.66 (br. t, 1H); 3.8 (br. t, 1H); 3.85 (m, 1H);4.17 (m, 1H); 4.2-4.4 (m, 3H); 7.1 (d, 1H); 7.13 (d, 1H); 7.2 (m, 2H);7.44 (s, 1H); 7.48 (s, 1H); 7.5 (d, 1H); 7.56 (d, 1H); 7.82 (br.t, 2H);10.59 (br., 1H); 10.96 (s, 1H).

EXAMPLE 2(S)-3-[2-[(methylsulfonyl)oxy]ethoxy]-4-(triphenylmethoxy)-1-butanolmethanesulfonate

A 1M THF solution of vinylmagnesium bromide (5.76 L, 5.76 mole, 1.96eq.) was cooled to -20° C. under N₂ and a catalytic amount of copperiodide was added (28.2 g, 0.148 mole, 0.05 eq.). The resultant mixturewas stirred at -20° C. for 5 minutes, and then a solution of(S)-Trityl-glycidol (929.0 g, 2.94 mole) in 3.2 L of dry THF was addeddropwise over 1.5 hours at -20° C. The reaction mixture was stirred for1 hour at -20° C. The reaction was quenched by cooling the reactionmixture to -30° C. and 5 L of an aqueous saturated solution of ammoniumchloride was slowly added. The organic layer was then extracted twicewith 1 L a 10% wt./volume solution of ethylenediaminetetraacetic acid,disodium salt dihydrate (EDTA) to remove any metals. The organic layerwas washed with 2 L of brine, dried (MgSO₄) and evaporated in vacuo togive 1061 g (96%) of (S)-1-(triphenylmethoxy)-4-penten-2-ol as an oil.

A 60% suspension of sodium hydride in mineral oil (268.9 g, 6.72 mole,1.5 eq.) was suspended in 2.8 L of dry THF under N₂ and a solution(S)-1-(triphenylmethoxy)-4-penten-2-ol (1543 g, 4.48 mole) in 5.6 L ofdry THF was added at room temperature. The resultant mixture was stirredat room temperature for 1.5 hours and then 770 mL (8.89 mole, 2.0 eq.)of freshly distilled allyl bromide was added over 20 minutes. Thereaction was heated to 45° C. for 1-2 hours. The reaction mixture wascooled to 15°-20° C. and 2 L of an aqueous saturated solution ofammonium chloride was slowly added to quench the excess base. Theresultant mixture was diluted with 1 L of ethyl acetate and 1 L of waterand the organic layer was isolated. The aqueous layer was back-extractedwith 500 mL of ethyl acetate and the combined organic layers were dried(MgSO₄) and evaporated in vacuo to give 1867 g (98%) of (S)-1,1',1"-[[[2-(2-propenyloxy) -4-pentenyl]oxy]methylidyne]tris [benzene]as a yellow oil.

(S) -1,1',1"-[[[2-(2-propenyloxy)-4-pentenyl]oxy]methylidyne]tris[benzene] (1281 g, 3.33 mole) wasdissolved in a solution of 4 L of anhydrous methyl alcohol and 3.6 L ofCH₂ Cl₂ and was cooled to -50° to -40° C. while bubbling N₂ through theviscous reaction solution. Sudan III indicator was added to the reactionand ozone was bubbled through the reaction mixture at -50° to -35° C.for 13 hours until the reaction turned from a peach color to a lightgreen/yellow color. The resultant reaction mixture was allowed to warmto 0° C. under N₂ and was then slowly added over 40 minutes to asolution of sodium borohydride (754 g, 19.9 mole, 6 eq.) in 2.5 Lethanol/2.5 L water while keeping the reaction temperature below 30° C.The reaction was then allowed to stir at room temperature overnight. Thereaction can be monitored by HPLC. The reaction mixture was cooled to10°-15° C. and was slowly added to 4 L of an aqueous saturated solutionof ammonium chloride at <20° C. The quenched reaction mixture was thenfiltered and the solids washed with 3 L of CH₂ Cl₂. The organic layerwas isolated and was washed with 3 L of an aqueous saturated solution ofammonium chloride and the aqueous layers were back-extracted with 1 L ofCH₂ Cl₂. The combined organic layer was dried (MgSO₄) and evaporated invacuo to give a 1361 g (>100%) of(S)-3-(2-hydroxyethoxy)-4-(triphenylmethoxy)-1-butanol as a oil.

(S)-3-(2-hydroxyethoxy)-4-(tripenylmethoxy)-1-butanol (500 g, 1.27 mole)was dissolved in 4.8 L of CH₂ Cl₂, was cooled to 0° C. under N₂, andtriethylamine (386.4 g, 532 mL, 3.81 mole, 3.0 eq.) was added.Methanesulfonyl chloride (396.3 g, 268 mL, 3.46 mole, 2.7 eq.) was thenadded dropwise over 30 minutes at <5° C. The resultant reaction mixturewas stirred at 0° to 5° C. for 1-2 hours and was monitored by HPLC. Thereaction mixture was diluted with additional CH₂ Cl₂ and was washedtwice with 2 L of water and 2 L of an aqueous saturated solution ofammonium chloride. The aqueous layers were back-extracted with 1 L ofCH₂ Cl₂ and the combined organic layer was dried (MgSO₄) and evaporatedin vacuo to give a crude solid that was recrystallized from 1/1heptane/ethyl acetate to give 615 g (88%) of(S)-3-[2-[(methylsulfonyl)oxy]ethoxy]-4-(triphenylmethoxy)-1-butanolmethane sulfonate in three crops as a solid. NMR. MS.

EXAMPLE 3 D-[2-iodoethoxy]-4-(tripenylmethoxy-iodobutone

Trityl chloride (175.2 g, 0.616 mole) was dissolved in 500 mL of CH₂ Cl₂under N₂. Triethylamine (71.9 g, 100 mL, 0.710 mole) was added and thenR,S-glycidol (50.0 g, 0.648 mole) was added, and the reaction solutionwas heated to a gentle reflux (42° C.) for 4 hours. The reaction wascooled to room temperature and was extracted twice with 250 mL of anaqueous saturated solution of ammonium chloride and then 250 mL ofbrine. The aqueous layers were back-extracted with 100 mL of CH₂ Cl₂ andthe organic layer was dried (MgSO₄) and evaporated in vacuo to givetrityl-glycidol as an oil that was recrystallized from ethanol to give104.4 g (54%) of trityl-glycidol as a solid.

A 1M THF solution of vinylmagnesium bromide (50 mL, 50 mmol, 2.0 eq.)was cooled to -20° C. under N₂ and a catalytic amount of copper iodidewas added (0.24 g, 1.26 mmol, 0.05 eq.). The resultant mixture wasstirred at -20° C. for 5 minutes and then a solution of trityl-glycidol(7.91 g, 25.0 mmol) in 40 mL of dry THF was added dropwise over 15minutes at -20° C. The reaction mixture was stirred for 3 hours at -20°C. and then was allowed to warm to room temperature and stir for 15minutes. The reaction was quenched by cooling the reaction mixture to-30° C. and 125 mL of an aqueous saturated solution of ammonium chloridewas slowly added. The resultant mixture was extracted with 200 mL ofethyl acetate. The organic layer was then extracted with an aqueoussolution of 0.93 g (2.50 mmol, 0.1 eq.) of ethylenediaminetetraaceticacid, disodium salt dihydrate (EDTA) in 125 mL of deionized water toremove any metals. The aqueous layers were back extracted with 50 mL ofethyl acetate and the combined organic layers were washed with 100 mL ofbrine, dried (MgSO₄) and evaporated in vacuo to give an oil that wasfiltered through silica (76 g) using 1.2 L of 3/1 hexanes/ethyl acetate.The filtrate was evaporated in vacuo to give 9.07 g of1-(triphenylmethoxy)-4-penten-2-ol as a light yellow colored oil (100%).

A 60% suspension of sodium hydride in mineral oil (6.13 g, 0.153 mol,1.5 eq.) was suspended in 175 mL of dry THF was added at roomtemperature. The resultant mixture was stirred at room temperature for1.5 hours and then 17.7 mL (0.204 mmol, 2.0 eq.) of freshly distilledallyl bromide was added via syringe. The reaction was heated to 45° C.for 1 hour. The reaction can be monitored by TLC or HPLC. The reactionmixture was cooled to 0° C. and 400 mL of an aqueous saturated solutionof ammonium chloride was slowly added to quench the excess base. Theresultant mixture was extracted with 800 mL of ethyl acetate and theorganic layer was washed with 500 mL of water. The aqueous layers wereback-extracted with 100 mL of ethyl acetate and the combined organiclayers were washed with 200 mL of brine, dried (MgSO₄) and evaporated invacuo to give 41.5 g (>100%) of1,1',1"-[[[2-(2-propenyloxy)-4-pentenyl]oxy]methylidyne]tris[benzene]asa yellow oil.

1,1',1"-[[[2-(2-propenyloxy)-4-pentenyl]oxy]methylidyne]tris[benzene](39.3g, 0.102 mol) was dissolved in a solution of 390 mL of anhydrous methylalcohol and 60 mL of CH₂ Cl₂ and was cooled to -50° to -40° C. whilebubbling N₂ through the viscous reaction solution. Ozone was thenbubbled through the reaction mixture at -50° to -40° C. for 80 minutesuntil the reaction turned pail blue in color. The resultant reactionmixture was allowed to warm to 0° C. under N₂ and then a solution ofsodium borohydride (23.15 g, 0.612 mole, 6 eq.) in 85 mL ethanol/85 mLwater was slowly added to quench the reaction while keeping the reactiontemperature below 10° C. The reaction was stirred in an ice bath for 30minutes and then was allowed to warm to room temperature and stirovernight. The temperature rose to 31° C. upon warming. The reactionmixture was diluted with 400 mL of an aqueous saturated solution ofammonium chloride and was extracted with 800 mL of ethyl acetate. Theorganic layer was washed with 400 mL of water and the aqueous layerswere back-extracted with 150 mL of ethyl acetate. The combined organiclayer was washed with 200 mL of brine and was dried (MgSO₄) andevaporated in vacuo to give a cloudy oil. This oil was recrystallizedfrom 2/1 hexanes/ethyl acetate in 3 crops to give 28.9 g of3-(2-hydroxyethoxy)-4-(triphenylmethoxy)-1-butanol (72%).

3-(2-hydroxyethoxy)-4-(triphenylmethoxy)-1-butonol (14.0 g, 35.7 mmol)was dissolved in 140 mL of CH₂ Cl₂, was 10 cooled to 0° C. under N₂, andtriethylamine (10.8 g, 14.9 mL, 0,107 mol. 3.0 eq.) was added.Methanesulfonyl chloride (11.0 g, 7.46 mL, 96.4 mmol, 2.7 eq.) was thenadded dropwise at <5° C. The resultant reaction mixture was diluted withadditional CH₂ Cl₂ (300 mL) and was washed with 200 mL of water and 200mL of an aqueous saturated solution of ammonium chloride. The aqueouslayers were back-extracted with 50 mL of CH₂ Cl₂ and the combinedorganic layer was washed with 100 mL of brine and was dried (MgSO₄) andevaporated in vacuo to give 18.4 g (94%) of3-(2-[(methylsulfonyl)oxy]ethoxy]-4-triphenylmethoxy)-1-butanol methanesulfonate as a white solid.

A solution of3-(2-[(methylsulfonyl)oxy]ethoxy]-4-triphenylmethoxy)-1-butanol methanesulfonate (5.0 g, 9.10 mmol) in 500 mL of reagent grade acetone wastreated with sodium bicarbonate (0.0770 g, 0910 mmol, 0.1 eq.) andsodium iodide (34.2 g, 0.228 mol. 25 eq.). The resultant mixture wasstirred at 50° C. under N₂ for approximately 16 hours. This reaction canbe monitored by HPLC. The acetone was removed from the reaction mixturein vacuo and the resultant solid was extracted into a 300 mL of ethylacetate/200 mL water mixture. The organic layer was washed with 200 mLmore water and the combined aqueous layer was back-extracted with 100 mLof additional ethyl acetate. The combined organic layer was washed with200 mL of a 10% aqueous solution of sodium sulfite (this wash removedthe yellow color), 100 mL of brine, was dried (MgSO₄), and wasevaporated in vacuo to give 5.45 g (98%) of3-[2-iodoethoxy]-4-(tripenylmethoxy-iodobutane as a clear oil. MS. NMR.

EXAMPLE 41-(tert-butyldimethylsilyloxy)-2-(3-iodopropyloxy)-4-(tert-butyldiphenylsilyloxy)-butane

To a methylene chloride (20 mL)/cyclohexane (100 mL) solution of thealcohol of Preparation 4 was added allyl trichloroacetimidate (17.82 g,88 mmols, 2.2 eq) under an N₂ balloon followed bytrifluoromethanesulfonic acid (50 μL/g of starting material, 0.92 mL).After 20 hours, the solution was filtered, and the filtrate was washedwith saturated aqueous NaHCO₃, water, and then brine. The organic layerwas collected and dried over MgSO₄. The solvent was removed to give anoil, which was purified by flash chromatography on silica gel elutingwith hexanes and increasing the polarity of the mobile phase to 5% ethylacetate in,hexanes over several liters to Yield 19.27 g of the alkylether as a light brown oil (97% yield). MS.

To a THF (60 mL) solution of the above allyl ether (14.16 g, 28.38mmols, 1 eq) was added 9-BBN (9-borabicyclo[3.3.1]nonane, 0.5M solutionin THF, 60 mL, 30 mmols, 1.1 eq) dropwise under nitrogen. After 3 hours,TLC (10% EtOAc in hexanes) of the reaction showed that the startingmaterial had been consumed. To this solution was added 3M aqueous NaOH(10.41 mL, 31.22 mmols, 1.1 eq) followed by slow (1.5 hr) dropwiseaddition of 30% hydrogen peroxide (10.3 mL, 90.82 mmols, 3.2 eq). Thereaction temperature during the peroxide quench was kept below 50 ° C.(ice bath).

After 30 minutes, sodium chloride was added until the solution wassaturated. The organic layer was removed; the aqueous layer wasextracted with ether; the combined organic layers were dried andfiltered; and the filtrate concentrated to give an oil. The crude oilwas purified by flash chromatography on silica gel eluting with 10%EtOAc/hexanes and increasing the polarity to 20% EtOAc/hexanes afterabout 1.5 liters of Solvent to yield 9.53 g of a light yellow oil (65%yield). MS.

To an anhydrous 0° C. ether (150 mL) solution of the above alcohol wasadded triethylamine (2.93 g, 28.91 mmols, 1.5 eq.) followed by dropwiseaddition of mesyl chloride (3.31 g, 28.91 mmols, 1.5 eq.) with vigorousstirring. After 3 hours at 0° C., TLC (10% EtOAc in hexanes) indicatedthe starting material was consumed. The reaction was diluted with ether,washed with water, brine, dried over MgSO₄, and the solvent removed. Theresulting oil was passed through a pad of silica eluting with 25%EtOAc/hexanes, and the eluant was concentrated. To an acetone (200 mL)solution of the resulting oil was added NaHCO₃ (0.17 g, 1.93 mmols, 0.1eq.), and NaI (28.88 g, 192.7 mmols, 10 eq.). After stirring 30 minutesat room temperature under a nitrogen atmosphere, the reaction was heatedto 50 ° C. with a water bath. After 2.5 hours, TLC (10% EtOAc inhexanes) indicated that the mesylate was consumed. The reaction mixturewas diluted with ether (500 mL), washed with cold saturated aqueous Na₂SO₃, water, brine, dried (MgSO₄), and the solvent removed. The resultingoil was passed through a pad of silica eluting with 5% EtOAc in hexanesto give the purified titled compound 10.3 g as a colorless oil (85%yield). ##STR18##

EXAMPLE 53,4-[(N,N'-1,1'-((2'ethoxy)-3'(O)-4'"-(hydroxy)-butane)-bis-(3,3'-indolyl)]-1(H)-pyrrole-2,5-dione(320283)

To a dimethylformamide (250 mL) solution ofbis-(3,3'-indolyl)-1-(methyl)-pyrrole-2,5-dione 301129(17.9 g, 52.5mmol, 3 eq) under nitrogen was added cesium carbonate (68.4 g, 4 eq). Tothe resulting suspension was added the iodide,1-(tert-butyldimethylsilyloxy)-3-(2-iodoethoxy)-4-(tert-butyldiphenylsilyloxy)-butane,(10.7 g, 17.5 mmol). The reaction stirred for 18 hours at roomtemperature. TLC (5% ethyl acetate/hexane) showed disappearance of theiodide. The reaction was poured into ethyl acetate (1200 mL) and washedwith 1N HCl (400 mL) followed by backwash with ethyl acetate (2×). Thecombined ethyl acetate portions were washed with saturated sodiumbicarbonate solution, brine (2×), dried (MgSO₄), filtered andconcentrated down in vacuo. Dimethylformate was removed by azeotropingwith xylene. The resulting red gum was slurried in dichloromethane andacetonitrile to give a solid suspension. It was concentrated down, moredichloromethane added, cooled and filtered to give a red solid. Some ofthe desired product was extracted from this solid by another triturationin dichloromethane and then in ethyl acetate. The filtrates wereconcentrated in vacuo and the resulting residue absorbed on silica andapplied to a large flash column. Dialkylated by-product was removed byelution with 5 hexane/1 ethyl acetate followed by elution of the productwith 3 hexane/1 ethyl acetate to provide 8.2 g (57%) of themonoalkylated product,3-[(N-1-(2-ethoxy-(3'"-(O)4'"-(tert-butyldiphenylsilyloxy)-1'"(tert-butyldimethylsilyloxy)-butane))-indol-3-yl]-4-[indol-3-yl]-1N(methyl)-pyrrole-2,5-dione.

To a methanol (450 mL) solution of the tert-butyldimethylsilyl ether,3-[(N-1-(2-ethoxy-(3'"-(O)-4'"-(tert-butyldiphenylsilyloxy)-1'"-(tert-butyldimethylsilyloxy)-butane))-indol-3-yl]-4-[indol-3-yl]-1N(methyl)-pyrrole-2,5-dione(8.2 g, 9.9 mmol) under nitrogen at 5 ° C. was added p-toluenesulfonicacid, monohydrate (0.16 g, 0.085 eq). After 2 hours, TLC (50% ethylacetate/hexane) showed the reaction to be nearly complete. The reactionwas quenched with solid sodium bicarbonate (0.14 g). The methanol wasremoved in vacuo. The resulting residue was dissolved in ethyl acetate,washed with 0.1N sodium hydroxide, brine (2×), dried (MgSO₄), filteredand concentrated in vacuo to give a red foam. This material was absorbedon silica and placed on a silica pad. Elution with 2 hexane/1 ethylacetate removed residual starting material followed by elution with 1hexane/1 ethyl acetate and 1 hexane/2 ethyl acetate to provide 6.4g(91%) of the alcohol,3-[(N-1-(2-ethoxy-(3'"-(O)-4'"-(tert-butyldiphenylsilyloxy)-1'"-(hydroxy)-butane))-indol-3-yl]-4-[indol-3-yl]-1N(methyl)-pyrrole-2,5-dione.

To an anhydrous ether (500 mL) solution of the alcohol,3-[(N-1-(2-ethoxy-(3'"-(O)-4'"-(tert-butyldiphenylsilyloxy)-1'"-(hydroxy)-butane))-indol-3-yl]-4-[indol-3-yl]-1N(methyl)-pyrrole-2,5-dione(6.36 g, 8.9 mmol) under nitrogen at 5° C. was added triethylamine (1.9mL, 1.5 eq) and methanesulfonyl chloride (1.0 mL, 1.5 eq). After 3hours, additional triethylamine (1.25 mL, 1.0 eq) and methanesulfonylchloride (0.7 mL, 1.0 eq) were added. After 1 hour, the reaction wasshown to be complete by TLC (50% ethyl acetate/hexane). The reaction wasdiluted with ether (250 mL), washed with water, 0.1N HCl and brine (2×).The ether was dried (MgSO₄), filtered, and concentrated in vacuo toprovide 7.0 g of mesylate, 3-[(N-1-(2-ethoxy-(3'"-(O)-4'"-(tert-butyldiphenylsilyloxy)-1'"-(methanesulfonyloxy)-butane))indol-3-yl]-4-[indol-3-yl]-1N(methyl)-pyrrole-2,5-dione.

To an acetone (200 mL) solution of the mesylate,3-[(N-1-(2-ethoxy-(3'"-(O)-4'"-(tert-butyldiphenylsilyloxy)-1'"-(methanesulfonyloxy)-butane))-indol-3-yl]-4-[indol-3-yl]-1N(methyl)-pyrrole-2,5-dione,(7.0 g, 8.9 mmol) under nitrogen was added sodium iodide (13.3 g, 10 eq)and sodium bicarbonate (75 mg, 0.1 eq). The mixture was stirred at 50°C. for 13 hours. The reaction was concentrated in vacuo, and the residuewas dissolved in ether and washed with 10% sodium sulfite solution. Thelayers were separated, and the ether portion washed with 10% sodiumsulfite solution, water, brine(2×), dried, and concentrated in vacuo.The residue was passed through a silica pad by eluting with 1 hexane/1ethyl acetate and 1 hexane/2 ethyl acetate to provide 7.6 g of theiodide,3-[(N-1-(2-ethoxy-(3'"-(O)-4'"-(tert-butyldiphenylsilyloxy)-1'"-(iodo)-butane))-indol-3-yl]-4-[indol-3-yl]-1N(methyl)-pyrrole-2,5-dioneas a red solid (quantitative yield for the two steps).

To a dimethylformamide (1 L) suspension of cesium carbonate (12.0 g, 4eq) under nitrogen was added the iodide,3-[(N-1-(2-ethoxy-(3'"-(O)-4'"-(tert-butyldiphenylsilyloxy)-1'"-(iodo)-butane))-indol-3-yl]-4-[indol-3-yl]-1N(methyl)-pyrrole-2,5-dione(7.6 g, 9.2 mmol), dissolved in dimethylformamide(25 mL) via syringepump over 65 hours. Three hours after the addition was complete, thereaction was concentrated in vacuo. The residue was dissolved in ethylacetate (700 mL), washed with water (2×300 mL), and the aqueous layerbackwashed with ethyl acetate (2×200 mL). The combined ethyl acetateportions were washed with brine (2×200 mL), dried (MgSO₄), filtered andconcentrated in vacuo to provide a purple residue. The material wasabsorbed onto silica and applied to a flash column. Eluted with 3hexane/1 ethyl acetate and then 1hexane/1 ethyl acetate to give 5.2g(82%) of the macrocycle,3,4-[(N,N'-1,1'-((2"-ethoxy)-3'"(O)-4'"-(tert-butyldiphenylsilyloxy)-butane)-bis-(3,3'-indolyl)]-1(H)--pyrrole-2,5-dione.

A suspension of the N-methyl maleimide,3,4-[(N,N'-1,1'-((2"-ethoxy)-3'"(O)-4'"-(tert-butyldiphenylsilyloxy)-butane)-bis-(3,3'-indolyl)]-1(H)-pyrrole-2,5-dionein 5N KOH (150 mL) and ethanol (300 mL) was stirred at room temperaturefor 65 hours and then for one hour at 60° C. The reaction wasconcentrated (150 mL) in vacuo, the residue suspended in water, cooledto 5° C., and acidified (pH 3) with concentrated hydrochloric acid. Thered aqueous suspension was extracted with ethyl acetate (4×200 mL),dried, and concentrated in vacuo to give 3.3 g of the crude anhydridealcohol,2,3-[(N,N'-1,1'-((2"-ethoxy)-3'"(O)-4'"-(hydroxy)-butane)-bis-(3,3'-indolyl)]-furan-1,4-dioneas a purple solid.

To a dimethylformamide (250 mL) solution of the anhydride,2,3-[(N,N'-1,1'-((2"-ethoxy)-3'"(O)-4'"-hydroxy)-butane)-bis-(3,3'-indolyl)]-furan-1,4-dione,(3.3 g, 7.5 mmol) under nitrogen was added1,1,1,3,3,3-hexamethyldisilazane (32 mL, 2 eq) and methanol (3 mL, 10eq). The reaction was stirred at room temperature for 16 hours and thenheated at 60° C. for 2 hours. The dimethylformamide was removed invacuo, and the resulting residue was dissolved in acetonitrile (250 mL).1N HCl (50 mL) was added. The reaction was stirred for 15 minutes. Thereaction was concentrated, partitioned between ethyl acetate (1 L) andwater (250 mL). The product was a solid that precipitated giving thealcohol maleimide,3,4-[(N,N'-1,1'-((2'-ethoxy)-3'"(O)-4'"-(hydroxy)-butane)-bis-(3,3'-indolyl)]-1(H)-pyrrole-2,5-dione,0.92(28%) of product. A small amount (50 mg) was absorbed on silica andapplied to a flash column. Eluted with dichloromethane, 5%acetonitrile/dichloromethane and then 10% acetonitrile/dichloromethaneto give 38 mg of analytically pure material. The ethyl acetate wasconcentrated and chromatographed to give an additional 8% of the crudeproduct. MS.

¹ H NMR (d₆ -DMSO): δ1.96 (1H, m); 2.09 (1H, m); 3.31 (1H, m); 3.40 (1H,m); 3.51 (1H, m); 3.62 (1H, m); 3.89 (1H, m); 4.18 (3H, m); 4.35 (1H,m), 4.68 (1H, t, J=2 Hz); 7.11 (2H, m); 7.19 (2H, m); 7.44 (1H, s) 7.46(1H, d, J=9 Hz); 7.51 (1H, s) 7.53 (1H, d, J=9 Hz); 7.79 (1H, d, J=8Hz); 7.83 (1H, d, J=8 Hz); 10.91 (1H, s).

We claim:
 1. A process which comprises(a) Alkylating a compound ofFormula (III): ##STR19## wherein, R² is --O-triphenylmethyl or--O-methoxytriphenylmethyl; Z is --(CH₂)_(n) --; and n is independently1, 2, or 3 with a lithium acetylide, a cerium acetylide, ororganometalic reagent selected from vinyl cuprate, vinyl aluminum, vinyltin, vinyl lithium, or vinyl Grignard; to produce a compound of theFormula (IV): ##STR20## (b) Reacting a compound of the Formula (IV) witha compound of the Formula: ##STR21## wherein R³ is halo, a protectedhydroxy, or combines with the adjacent carbon to form an olefin; R⁴ ischloro, bromo, or iodo; and n is independently 1,2, or 3; to form acompound of the Formula (V): ##STR22## (c) Converting the compound ofthe Formula (V) to a compound of the Formula (II): ##STR23## wherein: L¹is independently a leaving group; and (d) Alkylating a compound ofFormula (VIII): ##STR24## wherein R is independently hydrogen, halo, C₁-C₄ alkyl, hydroxy, C₁ -C₄ alkoxy, haloalkyl, nitro, NR⁵ R⁶, or--NHCO(C₁ -C₄ alkyl), R⁵ and R⁶ are independently hydrogen, metal,phenyl, benzyl, or combine to the nitrogen to which they are bonded toform a saturated or unsaturated 5 or 6 membered ring, and m isindependently 0, 1, 2, or 3, with a compound of Formula II, to produce acompound of the formula: ##STR25##
 2. The process of claim 1 wherein thecompound of Formula (VIII) is alkylated with a compound of Formula II inthe presence of about 0.5 to about 10 equivalents of Cs₂ CO₃.
 3. Aprocess which comprisesAlkylating a compound of Formula (IIIs):##STR26## wherein, R² is --O-triphenylmethyl or--O-methoxytriphenylmethyl; Z is --(CH₂)_(n) --; and n is independently1, 2, or 3 with a lithium acetylide, a cerium acetylide, ororganometalic reagent selected from vinyl cuprate, vinyl aluminum, vinyltin, vinyl lithium, or vinyl Grignard; to produce a compound of theFormula (IVs): ##STR27## (b) Reacting a compound of the Formula (IVs)with a compound of the Formula: ##STR28## wherein R³ is halo, aprotected hydroxy, or combines with the adjacent carbon to form anolefin; R⁴ is chloro, bromo, or iodo; and n is independently 1,2, or 3;to form a compound of the Formula (Vs): ##STR29## (c) Converting thecompound of the Formula (Vs) to a compound of the Formula (IIs):##STR30## wherein L¹ is independently a leaving group; and (d)Alkylating a compound of Formula (VIII): ##STR31## wherein R isindependently hydrogen, halo, C₁ -C₄ alkyl , hydroxy, C₁ -C₄ alkoxy,haloalkyl, nitro, NR⁵ R⁶, or --NHCO(C₁ -C₄ alkyl); R⁵ and R⁶ areindependently hydrogen, methyl, phenyl, benzyl, or combine to thenitrogen to which they are bonded to form a saturated or unsaturated 5or 6 membered ring; m is independently 0, 1, 2, or 3; with a compound ofFormula IIs, to produce a compound of the formula: ##STR32##
 4. Theprocess of claim 3 wherein the compound of Formula (VIII) is alkylatedwith a compound of Formula IIs in the presence of about 0.5 to about 10equivalents of Cs₂ CO₃.
 5. A process which comprises(a) Alkylating acompound of Formula (IIIr): ##STR33## wherein R² is --O-triphenylmethylor --O-methoxytriphenylmethyl; Z is --(CH₂)_(n) --; and n isindependently 1, 2, or 3 with a lithium acetylide, a cerium acetylide,or organometalic reagent selected from vinyl cuprate, vinyl aluminum,vinyl tin, vinyl lithium, or vinyl Grignard; to produce a compound ofthe Formula (IVr): ##STR34## (b) Reacting a compound of the Formula(IVr) with a compound of the Formula: ##STR35## wherein R³ is halo, aprotected hydroxy, or combines with the adjacent carbon to form anolefin; R⁴ is chloro, bromo, or iodo; and n is independently 1,2, or 3;to form a compound of the Formula (Vr) ##STR36## (c) Converting thecompound of the Formula (Vr) to a compound of the Formula (IIr):##STR37## wherein L¹ is independently a leaving group; and (d)Alkylating a compound of Formula (VIII): ##STR38## wherein R isindependently hydrogen, halo, C₁ -C₄ alkyl, hydroxy, C₁ -C₄ alkoxy,haloalkyl, nitro, NR⁵ R⁶, or --NHCO(C₁ -C₄ alkyl); R⁵ and R⁶ areindependently hydrogen, methyl, phenyl, benzyl, or combine to thenitrogen to which they are bonded to form a saturated or unsaturated 5or 6 membered ring; m is independently 0, 1, 2, or 3; with a compound ofFormula IIr, to produce a compound of the formula: ##STR39##
 6. Theprocess of claim 5 wherein the compound of Formula (VIII) is alkylatedwith a compound of Formula IIr in the presence of about 0.5 to about 10equivalents of Cs₂ CO₃.